In eukaryotic cells, DNA is packaged along with histone proteins in a nucleoprotein complex referred to as chromatin. The minimal repeating units of chromatin are the nucleosomes, which enable the folding of chromatin into fibers and higher order structures. Gene regulation on the chromatin level (‘epigenetics’) is achieved by nature through dynamic chemical modifications (‘marks’) of both DNA and histones, mediated by specialized ‘chromatin writer’ and ‘chromatin eraser’ enzymes (collectively referred to as ‘chromatin modifiers’). ‘Histone modifiers’ are proteins that attach (‘histone writers’) or remove (‘histone erasers’) one or more marks to or from histone proteins, respectively. ‘DNA modifiers’ are proteins that attach (‘DNA writers’) or remove (‘DNA erasers’) one or more marks to or from DNA, respectively. Examples include the pharmacologically relevant histone deacetylases (HDACs) and histone methyltransferases (HMTs). In combination, these modifications form local patterns (within the chromatin fiber, within a single nucleosome, and/or within a single histone), which are thought to serve as recruitment platforms for protein factors with specialized modules that recognize distinct marks (‘chromatin readers’ or ‘chromatin interactors’). ‘Histone readers’ or ‘histone interactors’ are proteins that recognize, or bind to, one or more marks on histone proteins, respectively. ‘DNA readers’ or ‘DNA interactors’ are proteins that recognize, or bind to, one or more marks on DNA, respectively. DNA and histone marks are important in cellular development and differentiation, and, accordingly, aberrant modifications and impaired combinatorial read-out are implicated in human diseases, especially cancer. As a consequence, chromatin biology and epigenetics have become the focus of many research initiatives in academia and the pharmaceutical industry. And yet, there is a rapidly growing mismatch between the amount of information that is generated by top-down epigenomic and proteomic approaches and the ability to systematically fill in the molecular details of the associated chromatin biochemistry. Despite expanding genomic information and proteomic information about histone sequences, variations, and types and abundance of natural modifications, and some enzymes responsible for modifications, knowledge of highly complex epigenetic mechanisms remains fragmentary, and there is a lack of effective biochemistry tools.
Aberrant posttranslational modification patterns on histone proteins as well as those found on DNA bases are often found in diseases. There is a need for understanding, assaying, and manipulating the underlying mechanisms as a prerequisite for the rational design of next-generation epigenetic drugs.